Long-term safety of inavolisib (GDC-0077) in an ongoing phase 1/1b study evaluating monotherapy and in combination (combo) with palbociclib and/or endocrine therapy in patients (pts) with <i>PIK3CA</i>-mutated, hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (BC).
Authors: Philippe L. Bedard, Melissa Kate Accordino, Andres Cervantes, Valentina Gambardella, Erika P. Hamilton, Antoine Italiano, Dejan Juric, Kevin Kalinsky, Ian E. Krop, Mafalda Oliveira, Cristina Saura, Peter Schmid, Nicholas C. Turner, Andreea Varga, Noopur Shankar, Jennifer Schutzman, Stephanie Royer-Joo, Miguel Valero Martin, Komal L. Jhaveri
Journal: Journal of Clinical Oncology (2022)

1052 Background: Dysregulating mutations in PIK3CA, encoding the PI3K p110α subunit, occur in ̃40% of HR+/HER2– BCs. Inavolisib is a PI3Kα-specific inhibitor that also promotes degradation of mutant p110α. It has demonstrated encouraging preliminary antitumor activity in pts with PIK3CA-mutated HR+ BC as a monotherapy, and in combo with other anticancer agents. Methods: We included pts from NCT03006172 on treatment ≥1 year with inavolisib alone (Arm A), or in combo with palbo + letrozole (letro) (B), letro (C), fulvestrant (fulv) (D), or palbo + fulv (E; + metformin in Arm F for pts with body mass index ≥30 and/or HbA1c ≥5.7%). Inavolisib was administered orally daily (PO QD) at 3, 6, 9, or 12 mg (3+3 dose-escalation design); letro at 2.5 mg PO QD; palbo at 125 mg PO QD for 21/28 days; and fulv at 500 mg intramuscularly every 4 weeks, in 28-day cycles until intolerable toxicity/disease progression. Safety was assessed by NCI-CTCAE v4. Results: 57 female pts were included (cutoff 07/26/21; N = 1, 18, 6, 12, 15, 5 in Arms A–F); median age: 57 years (range 33–80); median lines of prior therapy: 2 (1–7). All but 2 pts, both in Arm B (3 mg), were assigned the 9 mg inavolisib recommended phase 3 dose. Overall median treatment duration: 19 months (range 12–45); median inavolisib cumulative dose intensity, 95%. The most frequent treatment-related adverse events (AEs; in ≥20 pts/35%) were hyperglycemia (68%), stomatitis (68%; grouped terms), neutropenia (58%), diarrhea (51%), nausea (39%), alopecia (35%), and rash (35%; grouped terms). The most frequent treatment-related Grade (G) 3–4 AEs (≥2 pts/4%) were neutropenia (47%), hyperglycemia (16%), leukopenia (9%), thrombocytopenia (9%), lymphopenia (7%), weight decreased, and hypokalemia (4% each). G3–4 neutropenia, leukopenia, thrombocytopenia, and lymphopenia were all reported in palbo arms. One G5 AE of pleural effusion was reported (disease progression-related). 39 pts (68%) had ≥1 AE resulting in study treatment modification (drug interruption/dose reduction/treatment withdrawal); 11 (19%) had an inavolisib dose reduction and 2 (4%) discontinued treatment due to an AE (1 related G2 diarrhea, 1 unrelated G3 cerebrovascular disorder). AEs typically occurred during the first 6 months and tended to be less frequent in later cycles. No new safety signals were observed with long-term inavolisib use. Conclusions: These data indicate acceptable long-term tolerability. The safety profile of pts on study treatment with inavolisib alone or in combo with endocrine-based anticancer therapies for ≥1 year was similar to that reported for the overall study population. Updated data will be presented. A phase 3 study of inavolisib + palbo + fulv is enrolling (NCT04191499; INAVO120). Clinical trial information: NCT03006172.